1. Field of the Invention
The present invention relates to methods for selecting or matching a sport or sporting event to an individual (e.g., a sprint/power sport or an endurance sport) to increase their chances of success, optimizing the training programs of individuals, and for predicting the athletic performance of individuals. Certain embodiments of the invention relate to identifying specific gene(s) or alterations in the gene(s) that correlate with potential athletic performance. More particularly, the invention relates to methods of genotyping an individual with respect to the gene encoding the skeletal muscle protein, α-actinin-3 (ACTN3). In a specific embodiment, the ACTN3 genotype is determined for a single nucleotide polymorphism (SNP) site 1747 C>T.
2. Description of Related Art
In an increasingly competitive environment for athletic performance, talent search programs are on the rise to ensure that those with the potential to become an elite athlete are identified earlier in life to enable a head start in their efforts to reach their peak performance. These talent search programs are presently based on actual performance data and phenotypic predictors determined by the type of training to be undertaken, as well as the likely demands from the particular sport. One weakness of both current training programs and talent search criteria is the inability to determine whether an individual has already reached his/her performance potential, and so is unlikely to respond optimally to further training.
Another weakness of the current talent search programs, which is particularly relevant in countries with a relatively small population base in a large geographic area, is the opportunity for selection. An individual brought up in a environment with widespread access to sporting and coaching facilities is more likely to achieve success, and therefore more likely to come to the attention of coaches and talent scouts than a young individual with potential who resides in a relatively isolated location or who might otherwise have an underprivileged background. Similarly, individuals with potential to excel in lower profile sports such as rowing may be overlooked simply because these sports programs are less available in most schools. Again, this diminishes the chances of early identification and participation, leading to subsequent overlook by coaches and talent scouts. These are dilemmas facing sporting organizations such as the Australian Institute of Sport (AIS), since potential elite athletes are preferably selected and inducted into relevant training programs at a young age.
The possibility exists that linkages or associations of genotype or genotypic markers to certain physiological traits may contribute to or reduce performance in an elite athlete. Such methods may permit the development of DNA screens to assist in the selection of individuals with elite athlete potential. Such screens may help in overcoming some of the selection limitations of current talent search programs. In addition, such screening methods may assist in recognizing to whom and when a possibly small, but critical difference in an individual's training program should be made.
The α-actinins are a family of actin-binding proteins related to dystrophin and the spectrins (Blanchard, A. et al., Journal of Muscle Research & Cell Motility, 10, 280-289, 1989). In skeletal muscle, the family members α-actinin-2 and α-actinin-3 are major structural components of sarcomeric Z-lines, where they function to anchor actin-containing thin filaments in a constitutive manner (Beggs, A. H. et al., Journal of Biological Chemistry, 267, 9281-9288, 1992). However, recent studies suggest additional roles for the α-actinins in skeletal muscle.
It has been found that sarcomeric α-actinins bind to other thin filament and Z-line proteins including nebulin, myotilin, CapZ and myozenin (Nave, R. et al., FEBS Letters, 269, 163-166, 1990, Papa, I. et al., Journal of Muscle Research & Cell Motility, 20, 187-197, 1999, and Salmikangas, P. et al., Human Molecular Genetics, 8, 1329-1336, 1999), the intermediate filament proteins, synemin and vinculin (Bellin, R. M. et al., Journal of Biological Chemistry, 274, 29493-29499, 1999, and McGregor, A. et al., Biochemical Journal, 301, 225-233, 1994), and the sarcolemmal membrane proteins, dystrophin and β1 integrin (Hance, J. E. et al., Archives of Biochemistry & Biophysics, 365, 216-222, 1999, and Otey, C. A. et al., Journal of Biological Chemistry, 268, 21193-21197, 1993). These binding studies suggest that the α-actinins play a role in thin filament organization and the interaction between the sarcomere cytoskeleton and the muscle membrane. In addition, sarcomeric α-actinin binds phosphatidylinositol 4,5-bisphophate (Fukami, K. et al., Journal of Biological Chemistry, 269, 1518-1522, 1994), phosphatidylinositol 3 kinase (Shibasaki, F. et al., Biochemical Journal, 302, 551-557, 1994) and PDZ-LIM adaptor proteins (Pomies, P. et al., Journal of Cell Biology, 139, 157-168, 1997, and Pomies, P. et al., Journal of Biological Chemistry, 274, 29242-29250), suggesting a role in the regulation of myofiber differentiation and/or contraction.
In humans, the α-actinin-2 gene, ACTN2, is expressed in all skeletal muscle fibers, while expression of ACTN3, encoding α-actinin-3, is limited to a subset of type 2 (fast) fibers (North, K. N. et al., Nature Genetics, 21, 353-354, 1999). It has been recently demonstrated that α-actinin-3 is absent in ˜18% of individuals in a range of human populations and that homozygosity for a premature stop codon (577X) accounts for all cases of true α-actinin-3 deficiency states identified to date. An additional polymorphism (523R) occurs in linkage disequilibrium with 577X, but does not appear to exert a deleterious effect when expressed in the heterozygous state in coupling with 577R. Further, absence of α-actinin-3 is not associated with an obvious disease phenotype, suggesting that ACTN3 is redundant in humans (North, K. N. et al., 1999 Nature Genetics 21: 353-354).
Functional redundancy occurs when two genes perform overlapping functions so that inactivation of one of the genes has little or no effect on the phenotype (reviewed in Nowak, M. A. et al., Nature, 388, 167-171, 1997). In human skeletal muscle, α-actinin-2 expression completely overlaps α-actinin-3. ACTN2 and ACTN3 are also 80% identical and 90% similar (Beggs, A. H. et al., 1992, supra), and α-actinin-2 and α-actinin-3 are capable of forming heterodimers in vitro and in vivo, suggesting structural similarity and lack of significant functional differences between the two skeletal muscle α-actinin isoforms (Chan, Y. et al., Biochemical & Biophysical Research Communications, 248, 134-139, 1998). It is hypothesised that α-actinin-2 is able to compensate for the absence of α-actinin-3 in type 2 (fast) fibers in humans.